Field of the Invention
The present invention relates to treatments for cancer. More particularly, the present invention relates to methods for treating polyomavirus-positive cancers, such as Merkel cell polyomavirus-positive Merkel cell carcinoma.
Description of Related Art
Merkel cell carcinoma (MCC) is an aggressive cutaneous neoplasm presently treated by wide surgical excision with or without adjuvant radiation therapy. No defined chemotherapeutic regimen has proven effective, and those drug combinations in use are frequently based on MCC's histologic similarity to small cell lung carcinoma. Data from the Surveillance, Epidemiology, and End Results Program (SEER) of the National Cancer Institute indicates that MCC incidence has tripled from 0.15 in 1986 to 0.6 per 100,000 in 2006 resulting in approximately 1,500 new cases per year in the United States alone. MCC is a cancer of elderly (>65 years of age) and immunosuppressed populations that may be triggered by UV or ionizing radiation exposure. Given that these populations are increasing in developed countries, it is likely that MCC incidence will increase in coming years.
Merkel cell polyomavirus (MCV) was discovered in 2008 using digital transcriptome subtraction (DTS) during a directed search for the viral cause for MCC. Seven new human polyomaviruses have been described since 2007 using genomic technologies although MCV is currently the only polyomavirus so far established to be a cause for human cancer. DTS is a deep sequence-based method based on generation of high-fidelity (Hi-Fi) sequence datasets from tumor and control sample cDNAs. Known human cellular transcript sequences are “subtracted” from the HiFi dataset, leaving candidate sequences that might belong to a novel viral cDNA. DTS can also be used to quantitate relative cellular gene expression. MCV, similar to other polyomaviruses, is a double-stranded DNA virus that normally replicates as an episomal viral infection. MCV positive-MCC tumors are characterized by two distinct viral mutations: MCV genome integration into the human Merkel cell genome and truncation mutation of the MCV large tumor (LT) antigen gene. These mutations eliminate virus replication but leave the virus's tumor suppressor targeting domains intact. An additional important risk factor for MCC is loss of host immune surveillance, as occurs in AIDS, transplantation or aging, so that virus-positive tumor cells are not cleaved by an immune response. MCV is a common infection of human skin and MCV-positive MCCs represent an intriguing human tumor model in which mutations to the genome of a commensal virus, rather than the host genome, are required for the initiation of an aggressive cancer.
As with other polyomaviruses, differentially spliced LT and small T (sT) oncoproteins are expressed from the MCV T antigen early locus. MCV LT binds to transcriptional repressor retinoblastoma protein (RB1) family members through an N-terminal LXCXE motif that is not affected by MCV tumor-specific mutations. For SV40 polyomavirus, LT binding to RB1 with subsequent release of active E2F transcription factors is postulated to promote synthesis of genes required for entry into the S phase of the cell cycle. Cyclin E and E2F1 are positively regulated by E2F signaling and promote intracellular conditions for active DNA synthesis. SV40 LT also binds to and inhibits the pro-apoptotic tumor suppressor protein p53, but there is currently no evidence that MCV LT directly targets p53 in tumors since this corresponding region is deleted by tumor specific mutations. Other pro-survival pathways that might be targeted by MCV, such as the survivin oncoprotein, which is also regulated by RB1 signaling, had not been investigated. MCV sT, which is unaffected by tumor-specific mutations, transforms cells and activates cap-dependent translation by targeting the translation regulator 4E-BP1. When sT alone is knocked down, MCV-positive cells undergo cell cycle arrest whereas knockdown of both sT and LT together causes necroptotic cell death. Thus, both LT and sT oncoproteins are likely to contribute to the transformed phenotype of Merkel cell cancer.
Despite the growing knowledge of polyomaviruses and cancers caused by polyomaviruses, as well as a growing knowledge of the role of survivin in cancer proliferation, there is a dearth of treatments for cancers which are polyomavirus (+) and in which survivin is upregulated. Accordingly, there is a need in the art for treatments for polyomavirus (+) cancers in which survivin is upregulated.